Germline mutations in the MEN1 gene encoding menin predispose to endocrine tumors mainly of the parathyroids, anterior pituitary and entero-pancreatic endocrine tissues. We have investigated the molecular basis of this tissue specific tumorigenesis from menin loss in the pathogenesis of tumors of the pancreatic islet &#946;-cells (insulinoma). It is possible that the cause of the tissue-specificity is due to menin-mediated regulation of one or more tissue-specific factors such as those that control differentiation during embryogenesis. Therefore, we assessed the effect of menin loss or gain on the expression of factors that are known to control &#946;-cell differentiation. We found that the &#946;-cell differentiation factor HLXB9 (Mnx-1) is post-transcriptionally upregulated upon menin loss. HLXB9 causes apoptosis in the presence of menin, in MIN6 insulinoma &#946;-cells. Thus, dysregulation of HLXB9 predicts a possible mechanism for &#946;-cell proliferation in insulinomas resulting from the possible blockade of the pro-apoptotic activity of HLXB9 upon menin loss. These findings advance the understanding of how a ubiquitously expressed protein such as menin controls tissue-specific tumorigenesis. Moreover, our data reveal the mechanisms of action of HLXB9 and its targets in &#946;-cells. We also showed that HLXB9 is phosphorylated by the kinase GSK-3&#946;, both phospho-HLXB9 and GSK-3&#946; are expressed in mouse and human &#946;-cell tumors, and GSK-3&#946; inhibitors (such as lithium chloride) reduced cell proliferation and delayed cell cycle progression of mouse &#946;-cell tumor cell lines. We are interested in exploring whether lithium chloride treatment in the mouse model of MEN1 would reduce endocrine tumorigenesis. We are currently investigating the role of HLXB9 in sporadic pancreatic endocrine tumors, and the molecular mechanisms by which phospho-HLXB9 promotes tumorigenesis. These studies will provide insights into the pathways and actions of HLXB9 and its targets in normal &#946;-cells and in &#946;-cell tumors.